Rethinking The Relationship Between Protein And mRNA Expression

The central dogma of molecular biology states, “DNA makes RNA, and RNA makes protein.” Accordingly, protein expression has been believed to be primarily regulated by the production and degradation of mRNAs. Everyone believes it is a matter of course that protein expression is well-correlated thanks to mRNA expression.

However, recent studies have shown that their relationships are not so simple, but rather controversial. A recent review published in Cell [1] examined their relationships in various conditions and concluded that mRNA levels by themselves are often not sufficient to predict protein levels.

For example, a study cited in the review conducted a genome-wide, time-series survey using yeast that was subjected to osmotic stress and examined the correlation between the protein and mRNA expressions [2]. The correlation was not at all clear in two of the four most regulated pathways, and they only mentioned a possibility it “may be mainly due to a slight delay observed for the protein response compared to the RNA response.”

A potential solution comes from a Ph.D. project that aimed to develop an analytical framework for identifying specific gene groups that have a significant correlation between mRNA and protein from such genome-wide time-series data. The study mined the data of the previous study using yeast [2] provided by the first author Dr. Nathalie Selevsek at ETH Zürich, and made it possible to account for potential time delays in their relationships and classify genes according to the time delays and concordance of the time course of mRNA and protein expressions.

The framework was indeed effective in finding stronger correlations between mRNA and protein abundance among genes in the two pathways. Moreover, from the genome-wide data, it identified a pair of stress-responsive genes that showed a statistically significant correlation (Figure 1). The genes are distantly located in the same chromosome and encode different proteins both of which were reported to be important for cells to survive after stress. A concerted role of these genes would be vital in cellular stress response in yeast, and further studies are warranted to understand molecular mechanisms that enable such a long-distant interaction between the genes.

Figure 1: The two stress-responsive genes showed a highly similar time series of mRNA and protein abundance, particularly their evident increase within 30 min after the stress.

In addition, the study applied the analysis framework to another genome-wide time-series data in mammalian cells after stress and identified a group of genes related to cytoskeletons that show similar significant correlation. Another concerted role of these genes would be vital in cellular stress response in mammalian cells.

The study identified the two types of gene groups from the two genome-wide time-series data. On the other hand, such a significant correlation was not identified in the vast majority of genes, indicating relationships between mRNA and protein abundance are not as simple at all as suggested from the central dogma! Further studies are warranted to disentangle the relationship after accounting for various factors in addition to the time delays and concordance of the time course of mRNA and protein expressions examined in the study.